Project Summary Head and neck cancer is the fifth most common cancer in the United States, with an overall survival rate of around 50%. Compared to other subsites of head and neck cancer, the incidence of oropharyngeal cancer is increasing and has been intimately linked to human papillomavirus (HPV). Most oropharyngeal cancer patients receive standard therapy. However, clinical outcomes vary significantly and are difficult to predict. Thus, more robust prognostic biomarkers are needed to accurately stratify patients for the risk of treatment failures. The long-term goal of this research is to develop clinical prognostic assays and therapeutic agents for individualized oropharyngeal cancer treatment by focusing on microRNAs. MicroRNAs (miRNAs) are a family of small non-coding RNA molecules that collectively control the expression of thousands of protein-coding genes. miRNAs are extensively involved in tumorigenesis and they have deregulated expression in human cancers. Recent studies indicate that miRNAs are promising biomarkers and play critical regulatory roles in many types of cancer. However, the prognostic and therapeutic values of miRNAs in oropharyngeal cancer are poorly characterized to date. Our preliminary analysis has identified six miRNAs that are predictive of oropharyngeal cancer outcome. Here, we propose to significantly expand our preliminary study to identify new miRNA biomarkers by analyzing all oropharynx-related miRNAs in a large number of oropharyngeal tumors. These miRNA biomarkers will then be combined to build a robust model for significantly improved prognosis of oropharyngeal cancer. Further, the therapeutic potential of selected prognostic miRNAs will be evaluated by characterizing the roles of these miRNAs in cancer progression and treatment response.